Lethally irradiated tumor cell vaccines engineered to secrete GM-C SF (GVAX) showed promising efficacy in various models of melanoma, renal cell, prostate, and non-small cell lung, pancreatic, as well as head and neck squamous cell carcinoma, but due to the multiple immunological checkpoint blockades, GVAX as a monotherapy is unlikely to be clinically effective in advanced disease. GVAX was recently found to have uncertain efficacy in a phase III trial for advanced hormone refractory prostate cancer. The failure to overcome critical mechanisms of immune evasion by the tumor has been the major limitation of past immunotherapeutic strategies that were designed to primarily stimulate tumor-specific host immune responses. Among the many defined mechanisms for diminishing anti-tumor immune responses, regulatory T-cells (Treg), myeloid derived suppressor cells, and tolerizing dendritic cells (DCs) have been hypothesized as negative regulators that can prevent successful immunotherapy. One downstream consequence from some of these immune evasion checkpoint pathways is the limited number of activated antigen presenting cells (APCs) in the afferent arm of the immune system. Improved tumor cell vaccines that are able to overcome critical mechanisms of immune evasion by the tumor cell are needed.